This proposal draws together the collective experience and skills of researchers in the disciplines of Clinical Radiation Oncology, Radiation Biology, Veterinary Medicine, Biomathematics and Physics in a cohesive program focused on the improvement of radiotherapy practice through better understanding and application of knowledge relating to the effects of ionizing radiation on normal tissues and tumors. The major thrust of our research effort is in the optimal scheduling of radiation therapy and its integration with other modalities so as to maximize the probability of tumor control in relation to the tolerance of critical normal tissues. A corollary of this effort is research into the prediction of radiation response in individual patients. The program is divided into six research projects and four core components covering shared resources. By project, the research has the following objectives: 1) To study the kinetics of repair in acutely and late responding normal tissues and tumors in mice, and to use premature chromosome condensation techniques to study repair kinetics and residual damage in non-cycling cells; 2) To study isoeffect formulations, the volume effect, and decay of residual functional injury in preclinical large animal models, and to investigate the mechanisms of, and potential methods of protecting against, the exquisite radiosensitivity of primate serous salivary glands; 3) To study the modification of response of tumors in mice to irradiation by factors relating to their stromal elements, and to test the ability of appropriately scheduled irradiation to prevent the emergence of drug resistant tumor cell clones in a spheroid model; 4) To predict the response of tumors to irradiation and combined modality therapy by directly measuring their radio- and chemosensitivity, to test DNA crosslinks and the sister chromatid exchange assay as probes for hypoxic cells in vivo, and to derive the potential doubling time of human tumors by flow cytometric analysis; 5) To apply radiobiological concepts in clinical trials involving postoperative irradiation and definitive concomitant boost therapy for head and neck cancers, optimal scheduling of irradiation after, or integrated with, chemotherapy for advanced ovarian cancer, and hyperfractionated chest wall irradiation as part of the multimodal attack on advanced breast cancer; and 6) To improve the accuracy of dose specification in electron beam therapy by applying three dimensional inhomogeneity corrections and the development of specialized treatment techniques. The resources necessary to accomplish these objectives in terms of physical environment, patient numbers, and a large integrated research team are in place, and it is reasonable to expect that with renewed funding this research program will continue to exert a positive influence on the evolution of clinical radiation therapy practice.